Physical Sciences, Inc. (PSI), in collaboration with Memorial Sloan Kettering Cancer Center (MSKCC) and Lucid, Inc., proposes to investigate the use of combined reflectance confocal microscopy- polarization sensitive optical coherence tomography (RCM-PSOCT) for in vivo diagnosis of skin cancers. Both RCM and OCT are powerful technologies with proven success in human skin imaging. While RCM provides en face images with nuclear-level resolution in superficial skin, to depths of about 200 mm, OCT provides cross-sectional images with structural-level resolution in the deeper skin layers, to depths of at least 1 mm. Furthermore, PSOCT measures skin birefringence, and thus accurately differentiates between the dermal and epidermal skin layers. Therefore, the complementary capabilities of these two optical technologies may be exploited to offer a clinically comprehensive set of parameters for diagnostics which neither modality can provide by itself: presence and lateral spread of cancer, location of the dermo- epidermal junction and depth (stage) of invasion. Thus, this technology could help clinicians to provide more reliable diagnosis of suspicious skin lesions and significantly reduce the number of unnecessary biopsies. For a preliminary investigation of this powerful dual-mode imaging approach, a novel method for automated localization of the dermo-epidermal (DE) junction is proposed. In Phase I we propose to develop a benchtop instrument that will combine RCM and PSOCT within the same optical layout. Preliminary testing of this instrument will be performed on excised tissue specimens and on the normal skin of several volunteers. Based on Phase I conclusions, this instrument will be improved and a clinical prototype will be built and tested in a clinical setting on a larger number of normal and skin cancer patients during the Phase II study.